Declining Trends of Reoperations and Disease Behaviour Progression in Crohn’s Disease over Different Therapeutic Eras—A Prospective, Population-Based Study from Western Hungary between 1977–2020, Data from the Veszprem Cohort

Abstract Background and Aims Few population-based studies have investigated long-term surgery rates for Crohn’s disease [CD]. Our aim was to analyse disease progression and surgery rates in a population-based cohort over different therapeutic eras, based on the time of diagnosis: cohort-A [1977–1995], cohort-B [1996–2008], and cohort-C [2009–2018]. Methods A total of 946 incident CD patients were analysed (male/female: 496/450; median age at diagnosis: 28 years [y]; interquartile range [IQR]: 22–40]). Patient inclusion lasted between 1977 and 2018. Immunomodulators have become widespread in Hungary since the mid-1990s and biologic therapies since 2008. Patients were followed prospectively, with both in-hospital and outpatient records reviewed regularly. Results The probability of disease behaviour progression from inflammatory [B1] to stenosing or penetrating phenotype [B2/B3] significantly decreased (27.1 ± 5.3%/21.5 ± 2.5%/11.3 ± 2.2% in cohorts A/B/C, respectively, after 5 years; 44.3 ± 5.9%/30.6 ± 2.8%/16.1 ± 2.9% after 10 years, respectively; [pLogRank <0.001]). The probability of first resective surgery between cohorts A/B/C were 33.3 ± 3.8%/26.5 ± 2.1%/28.1 ± 2.4%, respectively, after 5 years; 46.1 ± 4.1%/32.6 ± 2.2%/33.0 ± 2.7% after 10 years, respectively; and 59.1 ± 4.0%/41.4 ± 2.6% [cohorts A/B] after 20 years. There was a significant decrease in first resective surgery risk between cohorts A and B [plog rank = 0.002]; however, no further decrease between cohorts B and C [plog rank = 0.665]. The cumulative probability of re-resection in cohorts A/B/C was decreasing over time (17.3 ± 4.1%/12.6 ± 2.6%/4.7 ± 2.0%, respectively, after 5 years [plog rank = 0.001]). Conclusion We report a continuous decline in reoperation rates and disease behaviour progression in CD over time, with the lowest values in the biologic era. In contrast, there was no further decrease in the probability of first major resective surgery after the immunosuppressive era.


Introduction
Crohn's disease [CD] is an idiopathic, progressive, inflammatory disorder of the gastrointestinal tract.Patients require anti-inflammatory treatment and often surgery, in order to avoid long-term bowel damage and disability. 1 The introduction of biologic therapies-antitumour necrosis factor-α [aTNF] therapies-has dramatically changed the therapeutic landscape of inflammatory bowel disease [IBD].Multiple randomied csontrolled trials [RCTs] have shown that aTNF therapies are effective in inducing and maintaining symptomatic remission and endoscopic healing among patients with moderate-to-severe CD. [2][3][4] Novel therapeutic approaches, including early and aggressive use of immunomodulators and biologic therapies, 5,6 aim to improve the natural disease course of CD by preventing disease progression and structural bowel damage caused by ongoing inflammation.
One of the most important disease outcomes in CD is the need for surgical interventions.Surgical resection rates varied largely over time across published studies, ranging from 25% to 61% at 5 years from diagnosis in a systematic review evaluating four decades of literature up to the early 2000s. 7][10] However, controversial results have also been published in recent years about the effectiveness of aTNF therapies in reducing surgery risk in inception cohorts.A recent, population-based, interrupted, time series study from Ontario, Canada, using health administrative databases, concluded that the marketplace introduction of infliximab was not associated with significant declines in the rates of intestinal resections or hospitalisations in CD patients. 11Indirect evidence is suggested from the recent Epi-IBD, populationbased, inception cohort, including unselected patients from multiple European, population-based cohorts. 12Although significantly more patients in Western European cohorts received biologic therapy and immunomodulators, 5-year outcomes including surgery and phenotype progression were similar across Western and Eastern Europe.
To date, surgery trends in CD in the biologic era have been investigated mainly in administrative databases, and most of these are lacking extensive disease phenotype and medical management data.Very few prospective, population-based cohorts are available from the biologic era, and even fewer provide long-term data on disease course and second surgical resection rates.
The Veszprem IBD cohort is a well-established, prospective, population-based, inception cohort from Veszprem County, Hungary, originally initiated in 1977.Previous data from the same cohort concluded that the reduction in surgical rates following the late 1990s was independently associated with increased and earlier use azathioprine in this CD cohort. 13he present work provides the complete assessment of the Veszprem IBD cohort encompassing more than 40 years, with the aim of analysing long-term disease phenotype progression, resective surgery rates, and second surgery [re-resection] rates over different therapeutic eras, including the latest 'biologic era', in a prospective, population-based setting.

Study population and design
This study is based on a prospective, population-based, inception cohort of CD patients from Veszprem Province, Hungary.Veszprem Province is an administrative region in western Hungary, and has a population of 353 068 residents [data from national census in 2011]. 14Patient inclusion lasted between January 1, 1977, and December 31, 2018.All patients in the investigated area who were diagnosed with CD in this period were included in the study.With each patient, diagnoses generated by in-hospital or outpatient visit records were reviewed thoroughly by an IBD expert gastroenterologist, using the Lennard-Jones 15 and the Copenhagen Diagnostic Criteria. 16Time of diagnosis was defined when necessary diagnostic tests [endoscopic, histological, and/or radiological evidence] were carried out to support the diagnosis of CD.In some cases, the final diagnosis was made years after the beginning of symptoms.Case validation and supervision were performed by the lead IBD specialist gastroenterologist in Csolnoky F. County Hospital upon data centralisation.Patient follow-up ended on December 31, 2020.
The primary outcome of the study was to assess and compare long-term disease phenotype and surgery rates in CD patients between different eras of treatment paradigms.The use of immunomodulator agents [thiopurines most commonly] became widespread in Hungary from the mid-1990s, 13

Data collection and reporting
Patients were followed prospectively from diagnosis to the end of the follow-up period or until the date of their emigration or death.Patient data were collected from four general hospitals in the province and accompanying gastroenterology outpatient units.Patient data were collected and reviewed every year, using public health records and questionnaires filled out by treating physicians for missing/additional data.The provincial IBD register data were centralised in Veszprem.The majority of patients [over 90% of CD patients] were monitored at the Csolnoky F. County Hospital in Veszprem, with a specialised IBD gastroenterology outpatient unit that serves as a secondary referral centre for IBD patients in the province.Since 2018, a cloud-based online interface-called National eHealth Infrastructure [EESZT]-has provides access to inpatient and outpatient medical records, extensive test results, and drug prescriptions, improving the appropriateness of the data collection in our cohort.Data on disease phenotype, medications, and surgical interventions were reported and updated yearly by the treating physician, using standardised data forms.Further detailed methodological description on data collection, case ascertainment, and geographical and socioeconomic background of the province is also available in our previous publications on this inception cohort. 17,18etailed demographic data were collected.Disease phenotype was evaluated at diagnosis and during follow-up based on the Montreal classification. [19]Data on medical therapy were collected from patient visit medical records and prescription records, and were updated yearly.Cumulative exposures to medications were evaluated.Time to disease behaviour change, time to first biologic therapy initiation, and time to surgical outcomes were collected.Death and time to death were also registered, and follow-up times were adjusted accordingly.
This work was prepared in adherence to the STROBE guidelines.

Statistical analysis
Continuous variables are presented as medians with interquartile range [IQR], whereas categorical variables are presented as numbers with percentages and standard deviation [SD].The t test or Mann-Whitney U test was used to compare continuous variables, and the χ 2 test or Fisher's exact test was used to compare categorical variables, as appropriate.Cumulative probabilities of medication use, disease phenotype change, and resective surgery were calculated using the Kaplan-Meier analysis, and the values were compared between groups by using the log-rank test.Multivariate regression analysis was performed to identify predictors of disease phenotype change and surgery.The following covariates were included in the statistical model: gender, age at diagnosis, era of diagnosis, disease behaviour, disease location, smoking status, and perianal manifestation.A p-value of <0.05 was regarded as statistically significant.
Statistical analyses were performed using the SPSS software v. 20.0 [Chicago, IL, USA].

Ethical statement
The study was approved by the Csolnoky F. Province Hospital Institutional Committee of Science and Research Ethics [193/2004, 0712/2009, and 2/2021].

Medical treatment
Cumulative exposure during the total follow-up to IBD specific groups of medications is detailed in Table 2

First resective surgery
The overall resective surgery rate was 40.6% [384/946 patients] in the total cohort.The cumulative probability of resective surgery in the total study population was 28.2 ± 1.5% after 5 years, 35.4 ± 1.6% after 10 years, 45.7 ± 2.0% after 20 years.The cumulative probability of first resective surgery in cohorts A/B/C were as follows: 33.3 ± 3.8%/26.5

Discussion
In the present study, we evaluated data from a well-established, large, prospective, population-based, inception cohort of CD patients, extending over a period of 40 years.We assessed 'real-life' disease course and long-term resective surgical outcomes over three different therapeutic eras.Our results showed that there was a significant decrease in the probability of first resective surgery with the widespread introduction of immunomodulator therapies; however, surgery risk did not show further decrease in the biologic era.Disease behaviour progression rate and the probability of second surgical resection [re-resection], however, showed a continuous decrease over the different therapeutic eras, being lowest in the most recent biologic era.
Based on a systematic review of population-based studies, surgical resection rates varied widely over time in the prebiologic era, ranging between 25-61% at 5 years, and 38-96% during the first 15 years after diagnosis. 7,20,21A populationbased cohort from Olmsted County, Minnesota, included incident CD patients diagnosed between 1970 and 2004.The cumulative probability of first major abdominal surgery from time of diagnosis was 38.2% [95% CI 32.5%-43.5%],47.6% [41.3%-53.3%],and 58.3% [50.6%-65.0%]at 5, 10, and 20 years, respectively.Results from the same cohort also showed that major abdominal surgery rates remained stable, with 5-year cumulative probabilities in 1970-1974 and 2000-2004 of 37.5% and 35.1%, respectively. 22Lakatos et al. published earlier results from the Veszprem IBD cohort including 506 incident CD patients diagnosed between 1977-2008.The 5-year probability of azathioprine use increased drastically, and results showed a significant reduction in the cumulative probability of resective surgery [1977-1998 vs. 1999-2008; plogrank = 0.022].Early azathioprine use was significantly associated with time to intestinal resection in a multivariate Cox analysis [HR: 0.43, 95% CI 0.28-0.65]. 13Similarly, results from the present study show a notable decrease in surgery risk with cohort B, which represents the period when the use of immunomodulators increased substantially.
The Dutch South Limburg [IBDSL] population-based cohort included 1162 CD patients, grouped into three eras: 1991-1998, 1999-2005, and 2006-2011. 23Over time,  the immunomodulator exposure increased from 30.6% to 70.8%.Similarly, biologic exposure increased from 3.1% [1991-1998]  Few population-based studies provide data on second resective surgery [or re-resection] rates.In the IBSEN cohort, from 1990 to 1994, 23% of the patients with first surgery required re-resection after 10 years of follow-up. 20he Olmsted County cohort report that the crude cumulative probability of second major abdominal surgery from time of first surgery was 30.8% [95% CI 22.6%-38.2%],44.9% [35.0%-53.3%],and 60.8% [45.8%-72.0%],at 5, 10, and 20 years, respectively, in the total cohort [1970-2004]. 22Second surgery risk from the Veszprem cohort is generally lower at all time points compared with data from the Olmsted county cohort, and quite similar to results from the IBSEN cohort when looking at the corresponding periods.Furthermore, we were able to assess and report time trends of the probability of second resective surgery.This is unique and to our knowledge is the first such analysis in a population-based cohort from the biologic era.We found a pronounced decrease in second resective surgery risk over time, in parallel with the introduction of immunomodulators and biologics.
Disease progression from B1 to B2/B3 phenotype slowed down significantly, with the 5-year probability decreasing from 27% to 11% in cohorts A [1977-1995] and C [2009-2018], respectively.A similar analysis was carried out in the IBDSL population-based cohort; however, authors did not observe a change in disease progression [B1>>B2/B3] over time [21.2% in the era 1991-1998 vs. 21.3% in the era 2006-2011, p = 0.93]. 23In the Epi-IBD pan-European cohort, 14% of patients diagnosed with B1 disease progressed to either B2 or B3 after 5 years, with no difference observed between Western and Easter European centres [plogrank = 0.41]; hence in Western centres, exposure to biologics was significantly higher. 12rug costs increased rapidly in the past decades with the widespread use of biologicals. 24The extent to which biologic agents offset these costs by preventing disease progression and reducing hospitalisations and surgery rates in the 'real-life' setting remains somewhat controversial.Reasons for the fact that our results also could not prove further decrease in first resective surgery rates in the biologic era may be multiple.In clinical practice, there is probably a greater variability in patient selection, therapeutic decisions, and patient follow-up than in RCTs, which may reduce treatment effectiveness at certain endpoints at the population level.Another factor may be the evolution of diagnostic tools and surgical attitudes.As is presented in our subanalyses [Supplementary Figures 1 and 2], patients having stenosing or penetrating disease at diagnosis, or having developed B2/B3 phenotype during follow-up, underwent surgery somewhat earlier and at a higher rate in more recent cohorts, whereas the number of patients undergoing surgery with L1 phenotype did not decrease in recent cohorts.We did observe a progressive decrease in re-resection rates and disease behaviour progression, showing the beneficial effect of biologics.One could also stipulate that second resective surgery [re-resection] rates more accurately reflect the beneficial effect of biologics, as predominantly patients with severe disease receive biologics and most of them probably already have organ damage to some extent, which the biologics cannot reverse.
We also analysed predictive factors for surgical outcomes and disease phenotype change.Similar to our results, in the Olmsted County cohort baseline disease characteristics were significantly associated with time to major abdominal surgery: isolated terminal ileal or ileocolonic disease [HR 3.1; 95% CI 1.8-5.4],current cigarette smoking [HR 1.7; 95% CI 1.1-2.7],and penetrating disease behaviour [HR 2.8; 95% CI 1.2-6.4]. 22In addition, colonic disease was reported to be a protective factor against resective surgery [HR 0.38; 95% CI 0.21-0.69]according to the European Collaborative Study Group [EC-IBD] cohort [1991-1993]. 25he strength of our study includes that the present work is one of the largest, prospective, population-based cohorts with a long-term follow-up of incident CD patients in a welldefined geographical area.This enabled us to evaluate time trends of long-term disease outcomes over different therapeutic eras.We applied strict and consistent diagnostic criteria with reliable case ascertainment, and centralised data capture with standardised data forms which were regularly updated during follow-up.Patients were consecutively enrolled and unselected.Case validation and data collection were supervised by the same lead IBD specialist gastroenterologist over the total observation period.A further advantage is the fact that our study offers the simultaneous analysis of disease phenotype evolution and second resective surgery [re-resection] rates as well, which is exceptional in current literature.Of note, we did not seek to analyse a direct association between exposure to specific therapies [aTNFs] and disease outcomes, but only to present trends on a populationbased level, reflecting disease management and therapeutic algorithms in the given therapeutic era.
Limitations of our study include the subtle differences in baseline characteristics between our cohorts.Substantial increase in incidence rates has been observed in this area since 1970; hence the sharply increasing number of subjects in our cohorts. 17 In conclusion, this present, population-based study shows a significant decrease in disease behaviour progression and second resective surgery [re-resection] rates in the more recent therapeutic eras, showing best outcomes in the biologic era.First resective surgery rates decreased with the widespread introduction of immunomodulators; however, there was no further decrease in the era of biologic therapies.Future, population-based studies are needed to assess how current treatment strategies can influence disease progression and/or surgery outcomes in the course of CD, at the population level.
Differences in disease phenotype at diagnosis can be at least partly explained by less diagnostic delay and improved diagnostic tools in IBD over time [e.g.cross-sectional imaging].
and biologic therapies have been commonly used and covered by the National Health Insurance Fund of Hungary since 2008.Therefore, we assessed the temporal trends in disease prognosis by dividing the study population into three consecutive A total of 946 patients (male/female: 496/450; mean age at diagnosis: 32.0 years[y] [SD: 14.8]) were diagnosed with CD in the inclusion period in Veszprem County.Based on time of diagnosis, n150 patients were classified into cohort A [1977-1995], 439 in cohort B [1996-2008], and 357 in cohort C [2009-2018].Median follow-up time for the entire cohort was 15 years [IQR: 9-21].For detailed patient characteristics and baseline disease phenotype, see Table 1.Among the three cohorts, there were subtle differences in gender distribution and age at diagnosis.In more recent cohorts, the number of male patients and mean age at diagnosis increased [p = 0.008, p = 0.003].Decreasing rates of active smoking was observed in latter cohorts [p <0.001].The proportion of patients with ileo-colonic [L3] disease location at diagnosis increased in cohort C [45.1%], compared with cohorts A and B [36.0% and 37.4%, respectively; p = 0.003].Stenosing [B2] disease behaviour rate was stable throughout the study period, whereas penetrating [B3] disease behaviour was somewhat less prevalent at diagnosis in cohorts B and C [19.1% and 21.6%, respectively] compared with cohort A [33.3%; p = 0.004].Presence of perianal manifestation at the time of diagnosis also decreased from the earlier to more recent cohorts [p = 0.006], whereas the rate of upper gastrointestinal [GI] manifestation at diagnosis increased [p <0.001].Of note, diagnostic delay between symptom onset and definitive diagnosis was also significantly higher in earlier cohorts [p = 0.013].

Table 2 .
Cumulative exposure to IBD specific groups of medications in incident Crohn's disease patients during the total follow-up 12 41.2%[2006-2011].In parallel, the hospitaliation rate decreased from 65.9% to 44.2% and surgery rate from 42.9% to 17.4% at 5 years, [both p <0.01].However, a propensity score-matched analysis was also carried out, where patients with immunosuppressive or biologic use within 2 years of diagnosis had a similar risk of hospitalisation, surgery, or disease phenotype progression compared with non-user controls [p >0.05 for all analyses], meaning that improvements were not significantly related to immunomodulator and biologic exposure.Authors stipulated that improvements in long-term outcomes in this cohort were mainly caused by factors other than changes in medical management, such as indications for hospitalisation and surgery, or disease monitoring.23Negativeresultswere also published by Murthy et al. in a population-based, interrupted, time series study from Ontario, Canada, using health administrative databases of over 20 000 CD patients between 1995 and 2012.11Authorspresented that prior to marketplace introduction of infliximab, there was a gradual 1.6% quarterly decline in the odds of intestinal resection.This rate of decline did not change significantly, and infliximab introduction was not associated with a statistically significant effect on intestinal resection rates [observed vs. counterfactual OR 1.10, 95% CI 0.81-1.50].One of the most recent, and largest, population-based, multicentre cohort is the Epi-IBD inception cohort including patients from 29 European cohorts, covering a background population of almost 10 million people.12Thestudy included 488 CD patients in total, diagnosed in 2010.Comparisons were made between Western and Eastern European centres,